Process for the stereoselective reduction of steroid enelactams

Abstract

The novel process of this invention involves the reduction of certain .DELTA.-5 steroidal alkenes to selectively produce either the 5.alpha. or 5.beta. reduction products. Particularly, this invention involves reduction of .DELTA.-5 steroidal alkenes using a rhodium based catalyst in the presence of hydrogen to selectively yield 5.alpha. steroids or alternatively reduction of .DELTA.-5 steroidal alkenes in an ionizing medium with a trialkylsilane to selectively yield 5.beta. steroids.

Claims

1. A process for the stereoselective reduction of a.DELTA.-5 steroidal enelactam of the formula I; ##STR51## wherein: Z is ##STR52## R is selected from H and C.sub.1 -C.sub.5 alkyl; R.sup.1 is selected from C.sub.1-5 alkyl and phenyl; and

A is any synthetically feasible substituent and which comprises

(b) refluxing said.DELTA.-5 steroidal enelactam in an ionizing medium in the presence of a trialkylsilane of the formula (R.sup.2).sub.3 SiH, wherein

R.sup.2 is selected from C.sub.1-6 alkyl and phenyl; provided that when Z is ##STR53## and R is selected from H and C.sub.1-5 alkyl, A is not C.sub.1-10 alkyl.

2. The process of claim 1 wherein A is selected from:

--H, protected hydroxy, acetoxy, hydroxy, carboxy, protected amino, amino, C.sub.1-10 alkyl, substituted or unsubstituted C.sub.1-10 alkynyl, aryl-substituted C.sub.1-10 alkyl, aryl, substituted aryl, aryl carbamoyl-substituted C.sub.1-10 alkyl, C.sub.1-10 alkylcarbonyl, arylcarbonyl, ether-substituted C.sub.1-10 alkyl, keto-substituted C.sub.1-10 alkyl, heteroaryl-substituted C.sub.1-10 alkyl, carboxylic ester, carboxamide, carbamoyl, substituted N-phenylcarboxamide ureido, C.sub.1-10 alkylureido, C.sub.1-10 alkylureido C.sub.1-5 alkyl, substituted or unsubstituted arylureido, substituted or unsubstituted arylureidoC.sub.1-5 alkyl, C.sub.1-10 alkanoyloxyC.sub.1-2 alkyl, C.sub.1-10 alkylcarbonylamino, alkanoylamidoalkyl, alkoxy, alkylthio, arylthio and substituted and unsubstituted aryl oxy.

3. The process of claim 2 wherein

(a) protected hydroxy is selected from: dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri-isopropylsilyloxy, and triphenylsilyloxy;

(b) protected amino is acetylamino;

(c) C.sub.1-10 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, and 1-methyl-4-isopropylhexyl;

(d) substituted or unsubstituted C.sub.1-10 alkynyl is selected from: phenylmethylenyl chlorophenylmethylenyl ethoxycarbonylphenylmethylenyl, carboxyphenylmethylenyl (((1,1-dimethylethyl) amino) carbonyl)phenylmethylenyl trimethoxyphenyl methylenyl, methoxyphenylmethylenyl, methylsulfonylphenylmethylenyl, biphenylmethylenyl, nitrophenylmethylenyl, aminophenylmethylenyl, acetylaminophenylmethylenyl, pivaloylaminophenylmethylenyl, phenoxyphenylmethylenyl, 2-imidazolyl methylenyl, and 2-thiazolylmethylenyl;

(e) aryl substituted C.sub.1-10 alkyl is selected from omega-phenylpropyl, and 1-(chlorophenoxy)ethyl;

(f) aryl is selected from phenyl, pyridinyl and pyrimidinyl;

(g) substituted aryl is selected from phenyl, pyridinyl and pyrimidinyl substituted with one to three substituents independently selected from:

(1) --H,

(2) --OH,

(3) --CH.sub.3,

(4) --OCH.sub.3,

(5) --S(O).sub.n --CH.sub.3, wherein n is selected from 0, 1, and 2,

(6) --CF.sub.3,

(7) halo,

(8) --CHO,

(9) CN, and

(10) --NHR.sup.7, wherein R.sup.7 is selected from:

--H, --C.sub.1-8 alkyl, --C.sub.1-6 alkylcarbonyl, --C.sub.1-6 alkylsulfonyl, and --C.sub.1-6 alkoxycarbonyl,

(h) aryl carbamoyl substituted C.sub.1-10 alkyl is 2-(4-pyridinylcarbamoyl)ethyl;

(i) C.sub.1-10 alkylcarbonyl is isobutylcarbonyl;

(j) arylcarbonyl is phenylcarbonyl;

(k) ether-substituted C.sub.1-10 alkyl is selected from 1-methoxy-ethyl, and 1-ethoxy-ethyl;

(l) keto-substituted C.sub.1-10 alkyl is selected from: 1-keto-ethyl, ketomethyl, 1-ketopropyl, and ketobutyl;

(m) heteroaryl-substituted C.sub.1-10 alkyl is omega-(4-pyridyl)-butyl;

(n) carboalkoxy is C.sub.1-10 alkylcarboxy selected from carbomethoxy and carboethoxy;

(o) carboxamido is selected from N,N-diisopropyl carboxamido, N-t-butyl carboxamido, N-(hydroxyphenyl) carboxamido, N-phenylcarboxamido, N-(aminophenyl) carboxamido, N-(carbomethoxy)phenyl carboxamido, N-(methoxycarboxy) phenyl carboxamido, N-acetamidophenyl-N-acetyl-carboxamido, N-acetamidophenyl-carboxamido, N-pivalamidophenyl carboxamido, N-isobutyramidophenyl carboxamido, N-(methyl),N-(diphenylmethyl) carboxamido, and N-(diphenylmethyl)-carboxamido;

(p) carbamoyl is selected from t-butylcarbamoyl and isopropylcarbamoyl;

(q) substituted N-phenylcarboxamido wherein the phenyl is substituted with 1 to 2 substituents selected from ethyl, methyl, trifluoromethyl, --F, --Cl, --Br, and --I;

(r) C.sub.1-10 alkanoyloxyC.sub.1-2 alkyl is selected from acetyloxymethyl, trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl,

(s) ureido is t-butylcarbonylamino ureido;

(t) C.sub.1-10 alkylureido is selected from: N-isopropylureido, and allylureido; and C.sub.1-10 alkylureido C.sub.1-5 alkyl, is selected from: N-t-butylureidomethyl, N-n-propylureidomethyl, and N-n-octylureidomethyl;

(u) substituted or unsubstituted arylureido is selected from: N-(fluorophenyl)ureido, and N-(methoxyphenyl)ureido; and substituted or unsubstituted arylureidoC.sub.1-5 alky is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl, N-(dichlorophenyl) ureidomethyl, N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl, N-thien-2-ylmethylureidomethyl, and 2-(ethoxyphenyl)ureidomethyl

(v) C.sub.1-10 alkylcarbonylamino is t-butylcarbonylamino;

(w) alkanoylamidoalkyl is selected from: trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl, (isobutylphenyl) propionamidomethyl, 8-carboxyoctanoylamidomethyl, bromohexanoylamidomethyl, hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl, isopropylthioacetamidomethyl, benzyloxyacetamidomethyl, carbomethoxyacetamidomethyl, triphenylprionamidomethyl, cyclohexylacetamidomethyl, methylcyclohexanecarboxamidomethyl, (3-hydroxy-4,4,4-trichlorobutyramido)methyl, and phenylthio-acetamidomethyl;

(x) alkyloxy is C.sub.1-8 alkyl ether optionally substituted with hydroxy, halo, C.sub.1-8 alkoxy, C.sub.1-6 alkenyl, or aryl,

(y) alkylthio is selected from: C.sub.1-8 alkylthio and C.sub.1-8 alkylthio substituted with phenyl; and arylthio is phenylthio; and

(z) substituted and unsubstituted aryl oxy is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenyloxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.

4. The process for the stereoselective reduction of claim 1 wherein Z is: ##STR54## and A is selected from carboxyl and hydroxyl.

5. The process for the stereoselective reduction of claim 4 wherein R is selected from H and methyl and R.sup.1 is methyl.

6. The process for the steroselective reduction of claim 1 wherein Z is: ##STR55## and A is selected from hydroxyl and protected hydroxyl.

7. The process for the stereoselective reduction of claim 6 wherein R is selected from H and methyl and R.sup.1 is methyl.

8. The process for the stereoselective reduction of claim 1 wherein Z is: ##STR56## and A is selected from alkyoxy and aryloxy.

9. The process of claim 8 wherein R is selected from H and methyl and R.sup.1 is methyl.

10. The process for the stereoselective reduction of claim 1 wherein Z is: ##STR57## A is C.sub.1-10 alkyl.

11. The process of claim 4 where R is selected from H and methyl.

12. The process of claim 1 in which the.DELTA.-5 steroidal enelactam is refluxed in an ionizing medium with a trialkylsilane to preferentially yield the 5.beta.-azasteroid.

13. The process of claim 12 where the ionizing medium is trifluoroacetic acid.

14. The process of claim 13 where the trialkylsilane is selected from di-t-butylmethylsilane and tri-t-butylsilane.